








key: cord-268389-0agwvsrv
authors: Kaminski, Monica A.; Sunny, Subin; Balabayova, Khayala; Kaur, Avneet; Gupta, Aanchal; Abdallah, Marie; Quale, John
title: Tocilizumab Therapy of COVID-19: A Comparison of Subcutaneous and Intravenous Therapies
date: 2020-09-28
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.09.1447
sha: 
doc_id: 268389
cord_uid: 0agwvsrv

Background The release of pro-inflammatory cytokines, resulting in cytokine storm syndrome, contributes to the morbidity and mortality associated with COVID-19 disease. This study aimed to compare the effects of intravenous (IV) and subcutaneous (SC) tocilizumab, an IL-6 receptor antagonist, on respiratory parameters and clinical outcome in patients with COVID 19. Methods We performed a retrospective cohort study of hospitalized patients with COVID-19 treated with either IV or SC tocilizumab from March 26, 2020 to May 18, 2020. Respiratory parameters seven days after receiving tocilizumab therapy were compared to baseline measurements. All patients were assessed until discharged from the hospital. Results Tocilizumab was administered to 125 patients: 65 received IV and 60 received SC therapy. At day seven, 52% of the patients in the IV group demonstrated improvement in respiratory parameters, compared to 28% in the SC group (P = 0.01). Mortality rates at days seven and 28 were 15% and 37%, respectively in the IV group and 17% and 50%, respectively in the SC group (P = NS). In-hospital mortality rate was 38% for the IV group versus 57% for the SC group (P = 0.04). More than 90% of patients in each group received corticosteroids, however significantly more patients in received convalescent plasma in the IV group. Conclusions At the doses used in this study, IV tocilizumab is preferred over SC therapy for the treatment of cytokine storm syndrome due to COVID-19.

The novel coronavirus, SARS-CoV-2, emerged in Wuhan, China in December 2019, and spread rapidly around the globe causing COVID-19 disease. As of July 2020, there have been 10 million J o u r n a l P r e -p r o o f cases reported, with 500,000 fatalities (https://www.who.int/emergencies/ diseases/novelcoronavirus-2019/situation-reports). While the majority of COVID-19 cases are mild and selflimiting, severe disease and death can occur. Risk factors for progression to critical illness and death include advanced age, underlying cardiac or renal disease, and obesity (Wu et al. 2020 , Petrillo et al. 2020 ). Progressive illness is characterized by massive alveolar damage, progressive respiratory failure, and multi-organ dysfunction (Xu Z et al. 2020 , Chen N et al. 2020 . Post-mortem analyses have shown an overactivation of TH17 and CD8 T cells with release of proinflammatory cytokines resulting in immune injury and cytokine storm.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been shown to be elevated in patients with severe disease (Chakraborty et al. 2020 , Luo et al. 2020 , Alghari et al. 2020 , and a potential target to reduce disease progression. Tocilizumab is a recombinant humanized monoclonal antibody that is directed specifically against the interleukin-6 receptor (IL-6R) and works by binding to both soluble and membrane-bound IL-6R, resulting in inhibition of IL-6-mediated signaling through these receptors (Le et al. 2018 , Antwi-Amoabeng et al. 2020 . Tocilizumab is FDA approved for use in patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, giant cell arteritis, and lifethreatening cytokine release syndrome associated with the use of chimeric antigen receptor T-cells.

Several studies have documented favorable outcomes following tocilizumab therapy in patients with severe COVID-19 disease. Xu et al reported the use of tocilizumab (administered as a one-time 400mg intravenous dose) in 21 patients with COVID-19 that resulted in no deaths, with 90% of their patients discharged home (Xu X et al., 2020) . Subsequent studies have also demonstrated benefit, with reductions in overall mortality, particularly in patients with more advanced disease (requiring mechanical ventilation) (Toniati et al., 2020 , Klopfenstein et al. 2020 , Rossotti et al., 2020 , Somers et al., 2020 , Guaraldi et al., 2020 . However, not all reports have been so favorable, especially in J o u r n a l P r e -p r o o f critically ill patients (Luo et al., 2020) . In addition, adverse effects (including superinfections and prolongation of hospital stay) have been noted (Rossotti et al., 2020 , Somers et al., 2020 , Guaraldi et al., 2020 .

Both intravenous (IV) and subcutaneous (SC) formulations of tocilizumab have been used to treat the cytokine storm due to COVID-19, with apparent equal effect (Guaraldi et al., 2020) . It is noteworthy that the pharmacokinetic profiles of the two formulations differ greatly. SC injection has an absorption half-life of approximately 4 days, resulting in a delayed achievement of Cmax (Tocilizumab package insert, 2017). In patients with rheumatoid arthritis, administration of 162 mg tocilizumab SC weekly and biweekly resulted in maximum serum levels of 9.3 ± 5.1 µg/mL and 5.8 ± 4.1 µg/mL, respectively (Lee et al., 2014) . In contrast, 8mg/kg of tocilizumab given IV weekly resulted in a maximum serum concentration of 136 ± 34 µg/mL (Lee et al., 2014) . Whether a more delayed but sustained effect following SC administration, or a more intensive but shorter-lived effect following IV administration, is preferable in managing cytokine storm is unknown.

In this report, the respiratory and clinical outcomes of patients treated with either IV or SC tocilizumab therapy for COVID-19 are compared.

Consecutive patients receiving tocilizumab for COVID-19 related illness between March 26,2020 through May 18, 2020 underwent standardized chart review. Our medical center, a large tertiary care facility located in Brooklyn, serves a predominantly minority and underserved population. All admitted patients with suspected or proven COVID-19 illness who were in respiratory distress (typically defined as a peripheral oxygen saturation ≤ 93 % on room air) were considered eligible for tocilizumab therapy.

Standard of care treatment developed at our institution included hydroxychloroquine 400 mg twice a day for one day followed by 200mg twice a day for an additional 4 days plus azithromycin 500mg once followed by 250mg oral once daily for an additional 4 days. Concomitant with tocilizumab therapy, short courses (typically 3-5 days) of corticosteroids were encouraged; corticosteroid dosing was often left to the discretion of the primary care providers.

Tocilizumab was administered at 400 mg IV, typically as single dose, based on initial reports (Xu X et al., 2020) . When the intravenous formulation was unavailable, the subcutaneous formulation was used. At our institution, a decision to use a SC dose of 324 mg (given as two simultaneous doses of 162 mg) was based on known pharmacokinetic data (Zhang et al., 2013) . It should be noted this was the same dosage used in another comparator study (Guaraldi et al., 2020) .

The study was approved by the Institutional Review Board at SUNY-Downstate Medical Center and the System to Track and Approve Research at NYC Health and Hospitals.

Patients treated with tocilizumab were retrospectively identified by review of pharmacy records. For each patient, a subsequent review of the electronic medical record was performed to obtain demographic, clinical, and laboratory information. The respiratory parameters for the 24 hours preceding the dose of tocilizumab and on days three and seven post-administration were recorded.

Two respiratory-based criteria were used to assess response to tocilizumab therapy: 1) to detect subtle changes in respiratory parameters, definitions of ventilatory response were taken to mirror National Healthcare Safety Network (NHSN) definitions for ventilatory-associated events. For each 24-hour period under review, the highest levels of oxygen requirement (i.e., FiO2) or PEEP that were sustained for at least one hour were recorded. Patients were considered to have ventilatory improvement if there was a decrease in FiO2 of ≥ 20% or PEEP of ≥ 3 cm H2O (with a PEEP setting of 0-5 cm H2O as the lowest setting). Patients were also considered to have responded if there was an incremental decrease in oxygen requirement reflected by a change from a higher to a lower category of oxygen support: mechanical ventilation (highest category), BiPAP/CPAP, high flow nasal canula, low-flow facemask, low flow nasal canula, and room air (lowest category).

2) to determine more overt changes in respiratory parameters at day 7, the disease severity scale employed by Li et al., 2020 was used. This ordinal scale consists of six clinical points: 6= death; 5= hospitalization with mechanical ventilation; 4= hospitalization with non-invasive ventilation or high-flow oxygen therapy; 3= hospitalization with other oxygen therapy; 2= hospitalization without oxygen therapy; and 1= discharged or achieved discharge criteria. Improvement was defined as a reduction by at least two points in the disease severity scale.

The following additional clinical information was recorded: 1) prior history of diabetes mellitus, hypertension, and ischemic heart disease; 2) receipt of corticosteroids and convalescent plasma during the 7-day observation period; and 3) duration of symptoms prior to tocilizumab administration. The following inflammatory markers prior to and within seven days post tocilizumab therapy were collected: C-reactive protein, D-dimers, ferritin, IL-6, lactate dehydrogenase, and procalcitonin.

Changes in basic laboratory values and positive cultures of blood were also noted during the 7-day observation period. Cytokine release syndrome grades were determined according to the criteria of Lee et al., 2018 . As of July 15, 2020, all patients had been discharged from the acute care medical service. Survival data was calculated from the day of tocilizumab administration to either death or discharge from the hospital. The primary endpoints were changes in ventilatory status at days three and seven following tocilizumab therapy. Secondary endpoints were survival rates at days seven, 28 and during the hospital stay. Fisher's exact test and student's t-test were used to compare categorical and continuous values, respectively, between groups. Student's t-test for paired values was used to compare pre-and posttocilizumab laboratory values. Survival curves were created using the Kaplan-Meier method and compared using the log-rank test. A P value of ≤ 0.05 was considered significant.

There were 125 patients included in the study; 65 received IV and 60 received SC tocilizumab.

Overall, 87 (70%) patients were African American persons. A nasopharyngeal swab was positive by RT-PCR for SARS-CoV-2 in 117 patients, with the remaining eight patients highly suspected of having COVID-19 illness. Overall, 82 patients were receiving supplemental oxygen and/or considered to have severe disease, and 43 were on mechanical ventilation and considered to have critical illness.

The baseline characteristics were generally comparable between the patients in the IV and SC groups (Table 1) ; there tended to be more females that received IV tocilizumab. At the time of IV tocilizumab therapy, 36 (55%) patients met grade 3 and 27 (42%) patients met grade 4 cytokine release syndrome criteria. Similarly, at the time of SC tocilizumab therapy, 32 (53%) patients met grade 3 and 26 (43%) met grade 4 cytokine release syndrome criteria.

Several laboratory values have been shown to be predictors of mortality in patients with COVID-19 (Garcia et al., 2020) , including blood levels of potassium, creatinine, D-dimers, lactate, and P/F ratios.

The baseline laboratory values for potassium, creatinine, and D-dimer were similar for the IV and SC groups (Table 1) . Lactate levels (2.4±1.6 vs. 2.1±1.1 mmol/L) and P/F ratios (148±101 vs. 148±89) were also similar between the IV and SC groups, respectively. The percentage of patients with known J o u r n a l P r e -p r o o f ischemic heart disease, also an indicator of higher mortality (Garcia et al., 2020) , was also similar in the IV and SC groups: 5 of 65 (8%) vs. 3 of 60 (5%), respectively. IL-6 levels have also been correlated with poor respiratory outcomes (Herold et al., 2020; and baseline levels were significantly higher in the group that received IV therapy vs. SC therapy (340 ± 655 vs. 124 ± 157 pg/mL, P=0.04). Concomitant use of corticosteroids was high in both groups: 94% in the IV group and 90% in the SC group. However, patients in the IV group tended to receive higher daily doses (≥ 500mg of methylprednisolone or equivalent) of corticosteroids than those in the SC group ( 

Using the six point disease severity scale to assess response to therapy (criterion two), more favorable outcomes at day seven were also noted in the IV group. At day seven, 16 (25%) of patients in the IV group had a two point reduction, compared to 6 (10%) of patients in the SC group (P=0.04).

Improvements in the cytokine release syndrome grades also favored the patients in the IV therapy group. Among the survivors at day seven, the average cytokine release syndrome grade fell from 3.33±0.55 to 2.78±1.23, P=0.0003) for the IV group. At day 7, the average cytokine release syndrome Laboratory values were also assessed in the survivors at day seven to determine if there were any differences in possible toxicities related to IV vs. SC tocilizumab therapy. Laboratory values at baseline were generally similar to values at day seven for patients in the IV group: white blood cell count (12.8±5.1 vs. 14.7±10.3 K/µL), absolute neutrophil count (10.7±4.6 vs. 12.0±9.5 K/µL), J o u r n a l P r e -p r o o f hemoglobin (11.5±2.3 vs. 11.0±2.2 g/dL), platelets (268±117 vs. 274±121 K/µL) and creatinine 1.85±2.34 vs. 1.51±1.76 mg/L). However, alanine aminotransferase levels did rise significantly at day seven, from 57.6±95 to 107±112 U/L (P<0.001). Laboratory values at baseline were all similar those at day seven for patients in the SC group: white blood cell count (13.2±6.4 vs. 13.8±8.5 K/µL), absolute neutrophil count (11.0±5.7 vs. 11.1±7.2 K/µL), hemoglobin (11.9±1.9 vs. 11.1±2.7 g/dL), In an attempt to identify factors that might predict improvement in respiratory parameters at day seven, baseline laboratory data were compared (Table 2) between the groups of patients showing and lacking (including death) improvement. C-reactive protein levels were significantly higher in patients in the IV group that did not respond (Table 2) Lastly, laboratory markers of inflammation were analyzed before and during the seven days following tocilizumab therapy to identify trends that correlated with response involving the respiratory parameters (Table 3) . For both responders and non-responders in the IV and SC groups, levels of C-reactive protein fell significantly following therapy (Table 3) . IL-6 levels rose in all groups, however this reached statistical significance only in the non-responders in the SC group. None of the other markers of inflammation collected within seven days following therapy were significantly different than pre-treatment values.

It is becoming increasingly evident that targeting the cytokine storm syndrome in patients with COVID-19 related illness can improve outcomes. Elevated IL-6 levels have been identified as a risk factor for adverse outcomes, including worsening respiratory status and death (Rossotti et al., 2020 , Ruan et al., 2020 . Considerable data has accumulated regarding the use of tocilizumab therapy for patients with serious or critical illness due to COVID-19. Tocilizumab has been found to be associated with improved outcomes in patients with COVID-19 related respiratory disease, particularly for patients with critical illness (i.e., requiring mechanical ventilation) (Rossotti et al., 2020 , Somers et al., 2020 . In one study, both IV (8mg/kg for two doses) and SC (324mg as a single dose) were found comparable in reducing mortality compared to standard of care (Guaraldi et al., 2020) .

In this report, we found divergent outcomes in patients administered IV vs. SC tocilizumab. We attempted to identify subtle differences in respiratory parameters during the first week of therapy by including National Safety Healthcare Network criteria of ventilator-associated events. As might be anticipated, given the pharmacokinetic differences of IV and SC tocilizumab, greater improvements in respiratory parameters were observed at three and seven days in the group of patients receiving IV therapy. This improvement in respiratory function subsequently translated into improved clinical outcomes -compared to those patients that received SC therapy, patients that received IV therapy had lower in-hospital mortality.

Over 90% of the patients in our study concomitantly received short courses of corticosteroids.

Corticosteroid dosing was higher in the group of patients that received IV tocilizumab, possibly contributing to the differences found with the SC group. However, doses of corticosteroids in both the IV and SC groups typically equaled or exceeded 6 mg of dexamethasone per day, a dose that has been found to be beneficial in reducing mortality in patients with advanced COVID-19 disease (Recovery collaborative group, 2020). The combination of corticosteroids and tocilizumab may have an additive effect in the treatment of cytokine storm syndrome (Ramiro et al., 2020) ; it is possible this effect is observed only with IV tocilizumab therapy.

Laboratory markers of inflammation are often used in the assessment of patients with COVID-19.

In addition to IL-6, elevated levels of C-reactive protein, D-dimers lactate dehydrogenase, and procalcitonin have been associated with poor prognosis (Wu et al., 2020 , Ruan et al., 2020 , Chen R et al., 2020 , Zhou et al., 2020 . In this report, patients that received IV tocilizumab that failed to have an improvement in respiratory parameters had higher levels of C-reactive protein than patients that did improve. It is likely that patients with extremely elevated levels of C-reactive protein may require a more aggressive strategy (e.g., multiple doses of tocilizumab). Laboratory markers of inflammation are also often used to gauge clinical response to therapy in patients with COVID-19. We did not find trends in markers of inflammation that differentiated patients that did or did not have improvement of respiratory parameters seven days after treatment. In our report, levels of C-reactive protein fell acutely in both patients that did and did not have improvement in respiratory parameters seven days following tocilizumab therapy. A decrease in C-reactive protein levels has been observed following tocilizumab therapy with or without corticosteroids (Xu X et al., 2020 , Rossotti et al., 2020 .

Our study has several limitations. In addition to being a single center study, as noted above, corticosteroids were administered to over 90% of our patients. More patients in the IV group received 

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